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Ozone in Medicine: Recent Advances on the Molecular Mechanisms Underlying Its Biological and Medical Action

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 14541

Special Issue Editor


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Guest Editor
Former Researcher Clinical Pharmacology Department, Marche Polytechnic University, 010118 Ancona, Italy
Interests: ozone; oxidative medicine; Nrf2; aging; hormesis; systems medicine

Special Issue Information

Dear Colleagues,

In light of the most recent scientific discoveries and the constant increase in authoritative literature in the field, we believe that a multidisciplinary approach is necessary for the better understanding and characterization of complementary and integrative techniques, such as those based on the administration of medical ozone.

In our opinion, a serious scientific evaluation is mandatory in order to help to clarify the molecular aspects underlying this method and, finally, to justify its potential usefulness for human health.

We will then retrace the path and the various passages that, from the first decades of the last century, accompanied the uses of ozone up to the most recent discoveries that, at the beginning of the third millennium, justified its application both in the prevention and treatment of many pathological conditions of third age, in addition to pathologies of the spine and skeletal muscle.

Life expectancy is constantly increasing and, despite a slight reduction in recent years due to the COVID-19 pandemic, it represents an event that, although favourable, will affect many conditions related to aging.

The recent discovery of common pathogenetic mechanisms and, above all, the involvement of the metabolic pathway of Nrf2 at the basis of cardiovascular, immunological, neurological and oncological disorders prevalent in the elderly population has opened new horizons regarding the prevention and possible integration of chemotherapy, pharmacology and surgery therapies.

We are convinced that oxidative medicine and ozone in particular can represent a surprising supplement, being relatively low cost and above all without adverse effects. It is also important to discuss its potential uses in dentistry and veterinary medicine that are continuously emerging around the world.

In summary, this Special Issue aims to clarify the possible molecular mechanisms underlying the cascade of messengers activated by an adequate oxidative stress, which, from a purely pharmacological point of view, are very far from the kinetic model represented by the Michaelis–Menten equation on drug–receptor interaction and which could be better defined according to the novel systems medicine approach.

Dr. Lamberto Re
Guest Editor

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Keywords

  • ozone
  • oxidative medicine
  • Nrf2
  • aging
  • hormesis
  • systems medicine

Published Papers (7 papers)

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Research

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16 pages, 2482 KiB  
Article
Modifications of Blood Molecular Components after Treatment with Low Ozone Concentrations
by Chiara Rita Inguscio, Barbara Cisterna, Flavia Carton, Elettra Barberis, Marcello Manfredi and Manuela Malatesta
Int. J. Mol. Sci. 2023, 24(24), 17175; https://doi.org/10.3390/ijms242417175 - 6 Dec 2023
Cited by 1 | Viewed by 947
Abstract
The ex vivo treatment of a limited volume of blood with gaseous oxygen–ozone (O2–O3) mixtures and its rapid reinfusion into the patient is a widespread medical procedure. O3 instantly reacts with the blood’s antioxidant systems, disappearing before reinfusion, [...] Read more.
The ex vivo treatment of a limited volume of blood with gaseous oxygen–ozone (O2–O3) mixtures and its rapid reinfusion into the patient is a widespread medical procedure. O3 instantly reacts with the blood’s antioxidant systems, disappearing before reinfusion, although the molecules formed act as messengers in the organism, inducing multiple antioxidant and anti-inflammatory responses. An appropriate dose of O3 is obviously essential to ensure both safety and therapeutic efficacy, and in recent years, the low-dose O3 concept has led to a significant reduction in the administered O3 concentrations. However, the molecular events triggered by such low concentrations in the blood still need to be fully elucidated. In this basic study, we analysed the molecular modifications induced ex vivo in sheep blood by 5 and 10 µg O3/mL O2 by means of a powerful metabolomics analysis in association with haemogas, light microscopy and bioanalytical assays. This combined approach revealed increased oxygenation and an increased antioxidant capacity in the O3-treated blood, which accorded with the literature. Moreover, original information was obtained on the impact of these low O3 concentrations on the metabolic pathways of amino acids, carbohydrates, lipids and nucleotides, with the modified metabolites being mostly involved in the preservation of the oxidant–antioxidant balance and in energy production. Full article
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12 pages, 1042 KiB  
Communication
Ozonated Oil in Liposome Eyedrops Reduces the Formation of Biofilm, Selection of Antibiotic-Resistant Bacteria, and Adhesion of Bacteria to Human Corneal Cells
by Valentina Gentili, Giovanni Strazzabosco, Niccolò Salgari, Alessandra Mancini, Sabrina Rizzo, Silvia Beltrami, Giovanna Schiuma, Fabio Casciano, Andrea Alogna, Daniela Passarella, Sergio Davinelli, Giovanni Scapagnini, Alessandro Medoro and Roberta Rizzo
Int. J. Mol. Sci. 2023, 24(18), 14078; https://doi.org/10.3390/ijms241814078 - 14 Sep 2023
Cited by 2 | Viewed by 1336
Abstract
The recent attention to the risk of potential permanent eye damage triggered by ocular infections has been leading to a deeper investigation of the current antimicrobials. An antimicrobial agent used in ophthalmology should possess the following characteristics: a broad antimicrobial spectrum, prompt action [...] Read more.
The recent attention to the risk of potential permanent eye damage triggered by ocular infections has been leading to a deeper investigation of the current antimicrobials. An antimicrobial agent used in ophthalmology should possess the following characteristics: a broad antimicrobial spectrum, prompt action even in the presence of organic matter, and nontoxicity. The objective of this study is to compare the antimicrobial efficacy of widely used ophthalmic antiseptics containing povidone-iodine, chlorhexidine, and liposomes containing ozonated sunflower oil. We determined the minimum inhibitory concentration (MIC) on various microbial strains: Staphylococcus aureus (ATCC 6538), methicillin-resistant Staphylococcus aureus (ATCC 33591), Staphylococcus epidermidis (ATCC 12228), Pseudomonas aeruginosa (ATCC 9027), and Escherichia coli (ATCC 873). Furthermore, we assessed its efficacy in controlling antibiotic resistance, biofilm formation, and bacterial adhesion. All three antiseptic ophthalmic preparations showed significant anti-microbicidal and anti-biofilm activity, with the liposomes containing ozonated sunflower oil with the highest ability to control antibiotic resistance and bacteria adhesion to human corneal cells. Full article
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12 pages, 2963 KiB  
Article
Mitochondrial Features of Mouse Myoblasts Are Finely Tuned by Low Doses of Ozone: The Evidence In Vitro
by Chiara Rita Inguscio, Elisa Dalla Pozza, Ilaria Dando, Federico Boschi, Gabriele Tabaracci, Osvaldo Angelini, Pietro Maria Picotti, Manuela Malatesta and Barbara Cisterna
Int. J. Mol. Sci. 2023, 24(10), 8900; https://doi.org/10.3390/ijms24108900 - 17 May 2023
Cited by 3 | Viewed by 1019
Abstract
The mild oxidative stress induced by low doses of gaseous ozone (O3) activates the antioxidant cell response through the nuclear factor erythroid 2-related factor 2 (Nrf2), thus inducing beneficial effects without cell damage. Mitochondria are sensitive to mild oxidative stress and [...] Read more.
The mild oxidative stress induced by low doses of gaseous ozone (O3) activates the antioxidant cell response through the nuclear factor erythroid 2-related factor 2 (Nrf2), thus inducing beneficial effects without cell damage. Mitochondria are sensitive to mild oxidative stress and represent a susceptible O3 target. In this in vitro study, we investigated the mitochondrial response to low O3 doses in the immortalized, non-tumoral muscle C2C12 cells; a multimodal approach including fluorescence microscopy, transmission electron microscopy and biochemistry was used. Results demonstrated that mitochondrial features are finely tuned by low O3 doses. The O3 concentration of 10 μg maintained normal levels of mitochondria-associated Nrf2, promoted the mitochondrial increase of size and cristae extension, reduced cellular reactive oxygen species (ROS) and prevented cell death. Conversely, in 20 μg O3-treated cells, where the association of Nrf2 with the mitochondria drastically dropped, mitochondria underwent more significant swelling, and ROS and cell death increased. This study, therefore, adds original evidence for the involvement of Nrf2 in the dose-dependent response to low O3 concentrations not only as an Antioxidant Response Elements (ARE) gene activator but also as a regulatory/protective factor of mitochondrial function. Full article
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14 pages, 931 KiB  
Article
Ozone Therapy versus Hyaluronic Acid Injections for Pain Relief in Patients with Knee Osteoarthritis: Preliminary Findings on Molecular and Clinical Outcomes from a Randomized Controlled Trial
by Cristiano Sconza, Berardo Di Matteo, Paolo Queirazza, Arianna Dina, Roberta Amenta, Stefano Respizzi, Giuseppe Massazza, Antonio Ammendolia, Elizaveta Kon and Alessandro de Sire
Int. J. Mol. Sci. 2023, 24(10), 8788; https://doi.org/10.3390/ijms24108788 - 15 May 2023
Cited by 13 | Viewed by 3693
Abstract
Ozone therapy (OT) is used for the treatment of multiple musculoskeletal disorders. In recent years, there has been a growing interest in its use for the treatment of osteoarthritis (OA). The aim of this double-blind randomized controlled trial was to evaluate the efficacy [...] Read more.
Ozone therapy (OT) is used for the treatment of multiple musculoskeletal disorders. In recent years, there has been a growing interest in its use for the treatment of osteoarthritis (OA). The aim of this double-blind randomized controlled trial was to evaluate the efficacy of OT compared with hyaluronic acid (HA) injections for pain relief in patients with knee OA. Patients with knee OA for at least three months were included and randomly assigned to receive three intra-articular injections of ozone or HA (once a week). Patients were assessed at baseline and at 1, 3, and 6 months after the injections for pain, stiffness, and function using the WOMAC LK 3.1, the NRS, and the KOOS questionnaire. Out of 55 patients assessed for eligibility, 52 participants were admitted to the study and randomly assigned into the 2 groups of treatment. During the study, eight patients dropped out. Thus, a total of 44 patients, reached the endpoint of the study at 6 months. Both Group A and B consisted of 22 patients. At 1-month follow-up after injections, both treatment groups improved statistically significantly from baseline in all outcomes measured. At 3 months, improvements remained similarly consistent for Group A and Group B. At 6-month follow-up, the outcomes were comparable between the 2 groups, showing only a worsening trend in pain. No significant differences were found between the two groups in pain scores. Both therapies have proven to be safe, with the few recorded adverse events being mild and self-limiting. OT has demonstrated similar results to HA injections, proving to be a safe approach with significant effects on pain control in patients affected by knee OA. Due to its anti-inflammatory and analgesic effects, ozone might be considered as a potential treatment for OA. Full article
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Review

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13 pages, 2137 KiB  
Review
Ozone as Redox Bioregulator in Preventive Medicine: The Molecular and Pharmacological Basis of the Low-Dose Ozone Concept—A Review
by Renate Viebahn-Haensler and Olga Sonia León Fernández
Int. J. Mol. Sci. 2023, 24(21), 15747; https://doi.org/10.3390/ijms242115747 - 30 Oct 2023
Viewed by 1426
Abstract
The best form of prevention against human infection through bacteria, viruses, and other parasites is ozone disinfection of wastewater and drinking water as a highly effective, well-known method. Various preclinical studies showed promising results, which are being revisited and reconsidered in times of [...] Read more.
The best form of prevention against human infection through bacteria, viruses, and other parasites is ozone disinfection of wastewater and drinking water as a highly effective, well-known method. Various preclinical studies showed promising results, which are being revisited and reconsidered in times of pandemics and led to interesting results in recent clinical trials and reports, as presented by the example of protective measures against COVID-19 in particularly vulnerable clinical personnel. The application of ozone in the form of the low-dose concept induces its regulation by interference of ozone or its peroxides into the redox equilibrium of the biological system, which finally results in the restoration of the glutathione equilibrium. The antioxidant system is activated, the immune system is modulated, and thus the defense mechanisms are improved. In patients with rheumatoid arthritis, repeated ozone treatments have led to new findings in “immunomodulation” through ozone. The more effective immune response is discussed as the response of innate immune memory and opens interesting aspects for complementary treatment of autoimmune diseases. Full article
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23 pages, 1197 KiB  
Review
The Biological and Molecular Action of Ozone and Its Derivatives: State-of-the-Art, Enhanced Scenarios, and Quality Insights
by Valter Travagli and Eugenio Luigi Iorio
Int. J. Mol. Sci. 2023, 24(10), 8465; https://doi.org/10.3390/ijms24108465 - 9 May 2023
Cited by 9 | Viewed by 2118
Abstract
The ultimate objective of this review is to encourage a multi-disciplinary and integrated methodological approach that, starting from the recognition of some current uncertainties, helps to deepen the molecular bases of ozone treatment effects on human and animal well-being and to optimize their [...] Read more.
The ultimate objective of this review is to encourage a multi-disciplinary and integrated methodological approach that, starting from the recognition of some current uncertainties, helps to deepen the molecular bases of ozone treatment effects on human and animal well-being and to optimize their performance in terms of reproducibility of results, quality, and safety. In fact, the common therapeutic treatments are normally documented by healthcare professionals’ prescriptions. The same applies to medicinal gases (whose uses are based on their pharmacological effects) that are intended for patients for treatment, diagnostic, or preventive purposes and that have been produced and inspected in accordance with good manufacturing practices and pharmacopoeia monographs. On the contrary, it is the responsibility of healthcare professionals, who thoughtfully choose to use ozone as a medicinal product, to achieve the following objectives: (i) to understand the molecular basis of the mechanism of action; (ii) to adjust the treatment according to the clinical responses obtained in accordance with the principles of precision medicine and personalized therapy; (iii) to ensure all quality standards. Full article
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14 pages, 1200 KiB  
Review
The Use of Medical Ozone in Chronic Intervertebral Disc Degeneration Can Be an Etiological and Conservative Treatment
by Anibal Martin Grangeat and Maria de los Angeles Erario
Int. J. Mol. Sci. 2023, 24(7), 6538; https://doi.org/10.3390/ijms24076538 - 31 Mar 2023
Cited by 7 | Viewed by 3265
Abstract
Degeneration of the intervertebral disc is one of the most frequent causes of lumbar pain, and it puts an extreme strain on worldwide healthcare systems. Finding a solution for this disease is an important challenge as current surgical and conservative treatments fail to [...] Read more.
Degeneration of the intervertebral disc is one of the most frequent causes of lumbar pain, and it puts an extreme strain on worldwide healthcare systems. Finding a solution for this disease is an important challenge as current surgical and conservative treatments fail to bring a short-term or long-term solution to the problem. Medical ozone has yielded excellent results in intervertebral disc pathology. When it comes to extruded disc herniation, ozone is the only etiological treatment because it stimulates the immune system to absorb the herniated portion of the nucleus pulposus, thus resolving discal extrusion. This work aims to examine the biomolecular mechanisms that lead to intervertebral disc degeneration while highlighting the significance of oxidative stress and chronic inflammation. Considering that ozone is a regulator of oxidative stress and, therefore, of inflammation, we assert that medical ozone could modulate this process and obtain inflammatory stage macrophages (M1) to switch to the repair phase (M2). Consequently, the ozone would be a therapeutic resource that would work on the etiology of the disease as an epigenetic regulator that would help repair the intervertebral space. Full article
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